Spicy food intake predicts Alzheimer-related cognitive decline in older adults with low physical activity

A plausible association exists among spicy food consumption, physical activity, and Alzheimer’s disease (AD) or cognitive decline, but it remains poorly investigated. We aimed to examined the association between spicy food and AD-related memory decline or global cognitive decline in older adults under the moderating effect of physical activity. Total 196 non-demented older adults were included. Participants underwent comprehensive dietary and clinical assessments including spicy food intake, AD-related memory, global cognition, and physical activity. The strength of spicy food was stratified into three categories: ‘not spicy’ (reference), ‘low spiciness’, and ‘high spiciness’. Multiple linear regression analyses were performed to examine the relationships between spicy level and cognition. The spicy level was the independent variable in each analysis; it was entered as a stratified categorical variable using the three categories. We found a significant association between a high level of spiciness in food and decreased memory (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β − 0.167, p < 0.001) or global cognition (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β − 0.122, p = 0.027), but not non-memory cognition. To explore the moderating effects of age, sex, apolipoprotein E ε4 allele-positivity, vascular risk score, body mass index, and physical activity on the associations between spicy level and memory or global cognition, the same regression analyses were repeated including two-way interaction terms between the spicy level and each of the six variables as an additional independent variable. An interactive effect was detected between a high level of spiciness in food and physical activity on the memory (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β 0.209, p = 0.029) or global cognition (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β 0.336, p = 0.001). Subgroup analyses showed that the association between a high level of spiciness in food and a lower memory (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β − 0.254, p < 0.001) and global score (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β − 0.222, p = 0.002) was present only in older adults with low physical activity, but not in older adults with high physical activity. Our findings suggest that spicy food intake is predictive of AD-related cognitive decline, i.e., episodic memory; this relationship is worsened by physically inactive lifestyle.

cognitive score and self-reported memory loss 9 . Additionally, preclinical studies have demonstrated that high capsaicin intake is associated with a neuronal, glutamate excitotoxic effect and an analgesic effect mediated via denervation of sensory nerves [10][11][12][13] .
Many studies have shown that physical activity has neuroprotective effects on the brain via various mechanisms 14 . A recent preclinical study of the mouse cerebral cortex revealed that physical activity lowers excessive brain glutamate levels in the brain and reduces its toxicity by increasing mitochondrial glutamate oxidation 15 . A meta-analysis found that physical activity was associated with a decreased incidence of AD 16 . Two prospective cohort studies found that physical activity was associated with better cognitive function, less cognitive decline, and a lower incidence of dementia 17,18 .
Despite possible associations between consumption of spicy foods, physical activity and Alzheimer's disease or cognitive decline, previous studies have investigated only the association between spicy food and physical activity [6][7][8][9][16][17][18] . No study has yet investigated other possible relationships or the moderating effects of their interactions. A human study showed that the effect of a Mediterranean-type diet on AD burden may vary by physical activity: participants not on such a diet with low physical activity had the highest AD burden, and those on such a diet who engaged in high physical activity had the lowest AD burden 19 . Such findings suggest interactions among spicy foods, physical activity, and AD-related cognitive decline.
Therefore, we examined the association between spicy food intake and AD-related memory decline or global cognitive decline in older adults without dementia. We explored the moderating effect of physical activity on the associations and determined whether physical activity affected on the associations between spicy food intake and AD-related memory decline or global cognitive decline.

Methods
Study design, setting and sample. The present study enrolled 196 adults without dementia (age between 65 and 90 years): 113 cognitively normal (CN) and 83 mild cognitive impairment (MCI) adults. The participants were recruited among individuals who attended in a dementia screening program at the memory clinic of Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea 2 . Volunteers were invited for an eligibility assessment and additional volunteers from the community were recruited through recommendations from other participants, family members, friends, or acquaintances 2 . The CN group consisted of participants with a Clinical Dementia Rating 20 score of 0 and no diagnosis of MCI or dementia 2 . All participants with MCI met the current consensus criteria for amnestic MCI, including memory complaints confirmed by an informant, objective memory impairment, preservation of global cognitive function, independence in functional activities, and the absence of dementia 2 . The age-, education-, and sex-adjusted z-score was < − 1.0 for at least one of the four episodic memory tests included in the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery, such as word list memory, word list recall, word list recognition, and constructional recall tests 2,21-23 . All participants with MCI had a Clinical Dementia Rating score of 0.5 2 . The exclusion criteria were the presence of a major psychiatric disorders, a significant neurological or medical illness, or a comorbidity that could affect cognitive functioning; illiteracy; visual/hearing difficulties or severe communication or behavioral problems that could make clinical examinations difficult; and the use of an investigational drug 2 .
Assessment of spicy level and other dietary habits. Participants were systematically interviewed for spicy foods they had eaten. To assess the strength of spicy food consumed among participants who ate spicy food at least once per week during the past year, participants were asked to indicate the age at which they began eating spicy food, as well as the strength of spicy food that they usually preferred.
The strength of spicy foods consumed were assessed by trained researchers in accordance with previously described methods 24 , using the following international standard scales for spicy levels in all forms of spicy foods: i.e., Scoville heat units (SHU), part-per-million (ppm) of capsaicin, and Gochujang hot taste units (GHU) for the hotness of Korean red chili paste or gochujang (https:// en. wikip edia. org/ wiki/ Scovi lle_ scale; https:// en. wikip edia. org/ wiki/ Gochu jang; https://e-ks. kr/ strea mdocs/ view/ sd; strea mdocs Id= 72059 20411 65823 29). As most Korean spicy foods are marked in units of spiciness i.e., SHU, ppm, and GHU, the intensity of spiciness was obtained through in-depth interviews. The strength of spicy food was stratified into three categories: 'not spicy' , 'low spiciness' (300-900 SHU; 20-60 ppm; levels 1 and 2 [mild to slightly hot] in GHU), and 'high spiciness' (≥ 900 SHU; ≥ 60 ppm; levels 3, 4, and 5 [medium to extremely hot] in GHU). A no spiciness level was used as a reference; the spicy levels were categorized into two groups based on the median quartile (low spiciness group vs. high spiciness group), consistent with the categorization based on the mean capsaicinoid content of foods commonly consumed in the Republic of Korea 25 . All participants were systematically interviewed to identify other dietary patterns (i.e., consumption of proteins, vegetables, fruits, salty foods, fatty foods, and fried foods) selected from the mini-dietary assessment 26 . The mini-dietary assessment tool was devised based on dietary guidelines and the food pyramid for Koreans; it provides a valid evaluation of overall dietary habits, including food components and dietary regulation of the diet 27 .
Clinical assessments. All participants underwent standardized clinical assessments by psychiatrists with more than 10 years of clinical experience based on the clinical assessment protocol, which incorporates the CERAD clinical and neuropsychological battery 21,22 . Trained neuropsychologists administered the neuropsychological assessment protocol incorporating the CERAD neuropsychological battery 23 to all participants. ADrelated cognitive domain was measured by the episodic memory, as the earliest cognitive change in AD [28][29][30][31][32][33] , and non-memory cognition for comparative purposes. The episodic memory score was determined by summing the scores of the four episodic memory tests (word list memory, word list recall, word list recognition, and construc- www.nature.com/scientificreports/ tional recall) in the CERAD neuropsychological battery. The non-memory score was calculated by summing the scores of the three non-memory tests (verbal fluency, modified Boston naming test, and constructional praxis) in the CERAD neuropsychological battery. The TS was generated by summing the scores of the seven tests in the CERAD neuropsychological battery, including verbal fluency, modified Boston naming, word list memory, constructional praxis, word list recall, word list recognition, and constructional recall 34 . Physical activities were evaluated using the Korean-version of the Physical Activity Scale for the Elderly (PASE) 35,36 , which has been tested for reliability and validity. Trained neuropsychologists assessed the frequency, duration and intensity of activities that participants performed with respect to leisure, household, and occupational activities during the previous week. The test items were weighted and summed to obtain a total physical activity score based on PASE sub-scores reflecting leisure, household, and occupational activities. A higher score indicated greater physical activity. Participants were categorized into two the physical activity groups based on the median quartile (high physical activity group vs. low physical activity group). Vascular risks (e.g., hypertension, diabetes mellitus, dyslipidemia, coronary heart disease, transient ischemic attack, and stroke) were assessed based on data collected by trained researchers during systematic interviews of participants and their family members 2 . The vascular risk score (VRS) was computed based on the number of vascular risk factors present and was reported as a percentage 2,37 . The Geriatric Depression Scale was used to measure the severity of depressive symptoms 2,38,39 . Annual income was categorized into below the minimum cost of living (MCL), above the MCL but below twice the MCL, and at or above twice the MCL Statistical analysis. Between-group comparisons of continuous data (demographic and clinical data) employed one-way analysis of variance. Categorical data were analyzed using chi-square or Fisher exact tests. Multiple linear regression analyses were performed to examine the relationships between spicy level and cognition. The spicy level was the independent variable in each analysis; it was entered as a stratified categorical variable using the three categories. We tested three models and controlling for the covariates in a stepwise manner. The first model included age, sex, and education as covariates; the second model included those covariates plus APOE4-positivity, clinical diagnosis, VRS, body mass index (BMI), Geriatric Depression Scale score, physical activity, annual income status, alcohol intake, smoking, and other dietary styles (e.g., consumption of proteins, vegetables, fruits, salty foods, fatty foods, and fried foods); and the third model included the covariates in the second model plus albumin, glucose, high-density lipoprotein-and low-density lipoprotein-cholesterol, zinc, iron, copper, and uric acid. Prior to multiple linear regression analyses, data normalities were checked using the Kolmogorov-Smirnov test for dependent variables. For the sensitivity analyses, the same analyses were performed for participants with CN and MCI participants because the cognitive tests may be less discriminatory in CN individuals. To explore the moderating effects of age, sex, APOE4-positivity, VRS, BMI, and physical activity on the associations between spicy level and cognition, which was significant in the analyses described above, the same regression analyses were repeated with inclusion of two-way interaction terms between the spicy level and each of the six variables; these constituted additional independent variables. The level of statistical significance was set to a two-tailed p value < 0.05. All statistical analyses were performed using SPSS Statistics software ver. 28 (IBM Corp., Armonk, NY, USA).
Ethics approval and consent to participate. This study protocol was approved by the institutional review board of the Hallym University Dongtan Sacred Heart Hospital and was conducted it in accordance with the recommendations of the current version of the Declaration of Helsinki. The subjects or their legal representatives gave informed consent.

Results
Characteristics of study sample. www.nature.com/scientificreports/ Associations between strength of spicy food and cognition. TS as global cognitive score was significantly differed among the stratified spicy strength levels. A high spiciness level was significantly associated with lower TS compared to the not-spicy level (β − 0.122, p = 0.027), but low spiciness level was not ( Table 2 and Fig. 1A). Regarding to cognitive domains, i.e., memory and non-memory domains, memory score was significantly differed among the stratified spicy strength levels, but non-memory score did not. A high spiciness level was also significantly associated with lower memory score compared to the not-spicy level (β − 0.167, p < 0.001), but low spiciness level was not ( Table 2 and Fig. 1B,C).

Moderation of the associations between spicy level and cognition.
The spicy level × physical activity interaction was significant in terms of the TS (β 0.336, p = 0.001) and memory score (β 0.209, p = 0.029), indicating that physical activity moderated the association between the spicy level and global and memory cognition (Table 3). Further subgroup analyses showed that a high spiciness level was significantly associated with a low TS (β − 0.222, p = 0.002) and memory score (β − 0.254, p < 0.001) in the low physical activity subgroup but not in the high physical activity subgroup (Table 4 and Fig. 2A,B). The interactions of spicy level with age, sex, APOE4-positivity, VRS, and BMI were not statistically significant (Table 3).

Sensitivity analyses. The sensitivity analysis of the participants with MCI and CN showed similar results
for memory score, but not for TS (Tables 5 and 6). A high spiciness level was significantly associated with a lower memory score compared to not-spicy level among participants with MCI (β − 0.325, p = 0.002) and CN (β − 0.238, p = 0.013), but a low spiciness level was not.   Table 3. Results of multiple linear regression analyses, including the interaction terms between the spicy level strata and age (or sex, or APOE4-positivity, or VRS, or BMI, or physical activity) in terms of predicting total score or memory score. Multiple linear regression model included spicy food level strata, age (or sex, or APOE4-positivity, or VRS, or BMI, or PASE) and the interaction between spicy food level strata and age (or sex, or APOE4-positivity, or VRS, or BMI, or PASE) treated as the independent variables; for all potential confound factors were treated as covariates; and total score or memory score treated as the dependent variable. APOE4 apolipoprotein ε4 allele, VRS vascular risk score, BMI body mass index, PASE physical activity scale for the elderly, PASE physical activity scale for the elderly.

Discussion
This study of adults without dementia showed that the consumption of food with a high level of spiciness was associated with greater AD-related cognition as indicated by the memory score, i.e., episodic memory; this association was moderated by the effect of physical activity. Previous studies have suggested that the consumption of spicy food is inversely associated with AD or related cognitive dysfunction [6][7][8] . Preclinical studies using AD-transgenic mice 6,8 indicated that the consumption of capsaicin, the pungent ingredient in chili peppers, reduces brain β-amyloid (Aβ) burden and rescues cognitive decline in AD-transgenic mice 6 . Daily capsaicin treatment attenuated cognitive and synaptic function, whereas a specific agonist of the transient receptor potential vanilloid 1 antagonist treatment did not, indicating that the activation of transient receptor potential vanilloid 1 by capsaicin rescues cognitive deficit in AD transgenic mice 8 . A human study also indicated that the consumption of a capsaicin-rich diet was associated with better cognition and lower serum Aβ levels in participants aged ≥ 40 years 7 .
In contrast, we found that a high spiciness level increased AD or related cognitive decline in older adults without dementia. This finding is consistent with the results in a longitudinal cohort study of 4582 adults over 15 years 9 , which revealed that higher chili intake (> 50 g/day) was positively associated with lower cognitive scores (as measured by the global cognitive score and self-reported memory loss) compared with non-consumers of chili. The authors of the longitudinal cohort study emphasized the differences between their findings and the finding reported in the human study noted above 7 ; they presumed that the differences were related to an age Table 4. Results of the multiple linear regression analyses concerning associations of spicy level strata with memory score according to physical activity subgroup. The first model included age, sex, and education as covariates; the second model included those covariates plus APOE4-positivity, clinical diagnosis, VRS, BMI, GDS, PASE, annual income status, alcohol intake, smoking, and other dietary styles (protein, vegetable, fruit, salty-and fatty-and fried-food); and, the third model included the covariates in the second model plus albumin, glucose, HDL-and LDL-cholesterol, zinc, iron, copper, and uric acid. APOE4 apolipoprotein E ε4 allele, VRS vascular risk score, BMI body mass index, GDS geriatric depression scale, PASE physical activity scale for the elderly.  www.nature.com/scientificreports/ discrepancy in terms of the quantity and frequency of chili consumption (i.e., participants with a high chili intake were younger than participants who did not consume chili) 9 . In the present study, all participants were older adults (mean age [SD] = 72.7 [6.0] years); there was no age difference between the spiciness groups (p = 0.602) ( Table 1). Thus, unlike in a former study 7 , age-related differences in spiciness did not seem to affect our findings. A preclinical study demonstrated the capsaicin-induced neurotoxic effect of high capsaicin intake 12 . The authors of that study suggested that capsaicin exerts an excitatory action by activating calcium ion channels, which causes a prolonged increase in intracellular calcium ion concentrations 10 that is associated with a glutamate excitotoxic effect in neurons 10 ; these interactions are the first events in a sequence that ultimately leads to cell death 12,13 . Furthermore, high doses of capsaicin have been used as an analgesic agent for pain management through chemical denervation of sensory nerves 11 . The physical activity status of our participants moderated the association between the spicy level and ADrelated cognitive decline, as indicated by the memory score, i.e., episodic memory. A significant association Table 5. Results of multiple linear regression analyses concerning associations of spicy levels with cognition in older adults with mild cognitive impairment. The first model included age, sex, and education as covariates; the second model included those covariates plus APOE4-positivity, VRS, BMI, GDS, PASE, annual income status, alcohol intake, smoking, and other dietary styles (protein, vegetable, fruit, salty-and fatty-and fried-food); and, the third model included the covariates in the second model plus albumin, glucose, HDL-and LDLcholesterol, zinc, iron, copper, and uric acid. APOE4 apolipoprotein E ε4 allele, VRS vascular risk score, BMI body mass index, GDS geriatric depression scale, PASE physical activity scale for the elderly.  www.nature.com/scientificreports/ was detected between a high spiciness level and worse episodic memory performance in participants with low physical activity, but not in participants with high physical activity. This finding may reflect the interactions among spicy levels, physical activity, and AD-related cognitive decline through neurotoxic effects. A preclinical study showed that physical activity increased mitochondrial glutamate metabolism in the mouse cerebral cortex, thereby lowing excessive brain glutamate and reducing its toxicity 15 . Additionally, many studies have shown that physical activity has a neuroprotective effect on the brain through various mechanisms 14 and may protect the brain from neurotoxic stimuli 41 . Therefore, the toxicity caused by a high spicy level was offset by these benefits of high physical activity but not by low physical activity.

Strengths and limitations.
To our knowledge, this is the first study to show an association between spicy level and AD-related cognition in humans using international and Korean official standard heat units (i.e., SHU, ppm, and GHU) for measuring the spicy levels, as well as the moderating effect of the spicy level on the association. The findings did not change after controlling for all potential confounders. The results were confirmed by sensitivity analysis after excluding participants who were CN and MCI. Our study had some limitations. First, because this was a cross-sectional study, causal relationships could not be inferred. Long-term prospective studies are needed. Second, there were raising some concerns about recall bias as we obtained the information on preference for spicy foods through clinical interviews. Approximately 42.3% of the study participants were diagnosed with MCI, which could raise some concerns about the accuracy of self-report on the preference for spicy food. However, participants with MCI have problems for their recent memory their remote memory is very well-preserved 42 . Thus, it is not likely that participants with MCI reported their preference for spicy food more erroneously because the self-report for their preference for spicy food mainly depends on remote memory rather than recent memory. As a lifestyle, dietary habits are not easily changed and persist in their lifetime, so they could report it accurately. In addition, even when we controlled for the clinical diagnosis as an additional covariate in Model 2, the results were still very similar. Moreover, the accuracy of the information of preference for spicy food was verified by reliable informants. Finally, we lacked adequate data on the frequency, amount and duration of cumulative exposure to spicy food; we cannot draw any significant associations. Further studies are needed.

Conclusion
Our findings suggest that spicy food intake is predictive of AD-related cognitive decline, i.e., episodic memory; this relationship is worsened by physically inactive lifestyle. Clinicians may need to monitor the consumption of spicy foods in older adults, along with their physical activity, to prevent AD or cognitive decline.

Data availability
The study data are not freely accessible because the IRB of the Hallym University Dongtan Sacred Heart Hospital prevents public sharing of such data for privacy reasons. However, the data are available on reasonable request after IRB approval. Requests for data access can be submitted to an independent administrative coordinator by e-mail (yoon4645@gmail.com).